The present invention relates to new methods of using certain xcex1-sulfonylamino hydroxamic acid inhibitors of matrix metalloproteinases in the treatment of diseases, conditions and disorders of the peripheral or central nervous system, including but not limited to Alzheimer""s disease, stroke/cerebral ischemia, head trauma, spinal cord injury, multiple sclerosis, amyotrophic lateral sclerosis, Huntington""s disease, Parkinson""s disease, migraine, cerebral amyloid angiopathy, AIDS, age-related cognitive decline; mild cognitive impairment and prion diseases, and pharmaceutical compositions useful therefor.
The compounds of the present invention are inhibitors of zinc metalloendopeptidases, especially those belonging to the matrix metalloproteinase (also called MMP or matrixin) and reprolysin (also known as adamylsin) subfamilies of the metzincins (Rawlings, et al., Methods in Enzymology, 248, 183-228 (1995) and Stocker, et al., Protein Science, 4, 823-840 (1995)).
The MMP subfamily of enzymes, currently contains seventeen members (MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-11, MMP-12, MMP-13, MMP-14, MMP-15, MMP-16, MMP-17, MMP-18, MMP-19, MMP-20). The MMP""s are most well known for their role in regulating the turn-over of extracellular matrix (ECM) proteins and as such play important roles in normal physiological processes such as reproduction, development and differentiation.
In the central nervous system, the ECM not only serves structural and adhesive functions but also stimulates intracellular signaling pathways in response to association of the matrix with cell surface proteins. (Yong et al., Trends in Neuroscience, 21, 75-80 (1998)) Excessive expression of MMP""s is believed to contribute to the pathogenesis of tissue destructive diseases such as arthritis, multiple sclerosis (MS) and cancer, conditions where inflammation and invasive processes play important roles. In Alzheimer""s Disease (AD) and age-matched control samples, the expression of MMP""s, particularly MMP-9 and MMP-2, is increased. The link between MMP""s, AD and the ECM is supported by in vitro and in vivo evidence. In clinical samples taken from stroke, MS, amyotrophic lateral sclerosis (ALS) patients, increased expression of MMP""s has also been documented. In AD, astrocytes produce inflammatory mediators and ECM proteins which surround neuritic plaques.
Like other members of the matrix metalloproteinase family, MMP-2 (72 kDa type IV collagenase or Gelatinase A) and MMP-9 (92 kDa type IV collagenase or Gelatinase B) are calcium-requiring, zinc containing endopeptidases which are secreted from cells in a latent pro-enzyme form (Yong et al., supra). These MMP""s attack type IV collagen, laminen and fibronectin, the major components of the ECM surrounding cerebral blood vessels. Because of the dire consequences of inappropriate or unbalanced activity, they are tightly regulated by three independent mechanisms: proenzyme activation, gene transcription and inhibition by their endogenous inhibitor TIMP-1 (Borden and Heller, Critical Reviews in Eurkaryotic Gene Expression, 7, 159-178, (1997)). The expression of MMP-9 is induced by growth factors and inflammatory cytokines in an NF-xcexaB and AP-1 dependent manner (Bond et al., FEBS Letters, 435, 29-34, (1998)). MMP-2 is generally constitutively expressed; however, its mRNA can be modulated by some of the same factors which modulate MMP-9 expression (Gottschall and Deb, Neuroimmunomodulation, 3, 69-75, (1996)).
Additionally, in AD hippocampus, MMP-9 protein is increased as much as four-fold (Backstrom et al., J. Neurochemistry, 58, 983-92 (1992)). The enzyme is predominantly found in its latent or proenzyme form in close proximity to extracellular amyloid plaques (Backstrom et al., J. Neuroscience, 16, 7910-19 (1996)). Similar observations were made in aged beagles. In amyloid-positive samples, statistically significant increases in latent MMP-9 were seen as compared with amyloid-negative samples (Lim et al., J. Neurochemistry, 68, 1606-11 (1997)).
The link between MMPs, AD and the ECM is supported by additional evidence (Perlmutter et al., J. Neuroscience Res., 30, 673-81 (1991); Brandan and Inestrosa, Gen. Pharmacology, 24, 1063-8 (1993); Eikelenboom et al., Virchows Archiv, 424, 421-7 (1994); Luckenbill-Edds, Brain Res. Revs., 23, 1-27 (1997)). Laminin is induced by brain injury and co-localizes with amyloid deposits in AD. In AD tissue, native human laminin was localized in large punctate, extracellular deposits which co-localize with plaques. Antibodies to the neurite-outgrowth promoting domains of laminin B2 or A chains localize to glia or capillary basement membranes, respectively. In control brains, laminin immunoreactivity is only found in capillaries (Murtomaki et al., J. Neuroscience Res., 32, 261-73 (1993)). In a murine model of neurodegeneration (Chen and Strickland, Cell, 91, 917-25 (1997)), kainic acid challenged neurons secrete tPA. This initiates a cascade of proteolytic events beginning with conversion of plasminogen to plasmin and ending with degradation of laminin and subsequent death of neurons. Plasmin is a known activator of MMP-9 which could be part of this proteolytic cascade resulting in the eventual destruction of neurons.
In PC12 cells, laminin or specific laminin peptides are capable to stimulating MMP secretion and this mechanism is linked to laminin-mediated neurite outgrowth (Weeks et al., Exp. Cell Res., 243, 375-82 (1998)). There has been a suggestion that these specific laminin sites may only be exposed in the basement membrane as observed in AD (Kibby et al., Proc. Nat. Acad. Sci., 90, 10150-3 (1993)). Further deposition of Axcex2 could be nucleated by these laminin fragments which are found in neuritic plaques. Therefore, interfering with degradation of laminin could have the outcome of preserving the ECM, enhancing neuronal survival, and eliminating at least one protein which may act as a seed for nucleation of Axcex2.
Elevated expression of MMP-9 and MMP-2 has also been documented in stroke, MS and ALS. After focal ischemia in humans, MMP-9 is markedly elevated in the infarcted tissue at two days post-infarction and remained elevated for months. Increases in MMP-2 were subtle at 2-5 days and like MMP-9, remained marked and significant for months (Clark et al., Neuroscience Letters, 238, 53-6 (1997)). Analysis of brain and spinal cord samples from ALS patients identified major bands of enzyme activity as MMP-2 and MMP-9; MMP-2 in astrocytes and MMP-9 in pyramidal neurons of the motor cortex and motor neurons of the spinal cord. Increases in MMP-9 were observed in ALS frontal and occipital cortices and spinal cord versus control samples. The high level of MMP-9 and its possible release at the synapse may destroy the structural integrity of the surrounding matrix thereby contributing to the pathogenesis of ALS. (Lim et al., J. Neurochemistry, 67, 251-9 (1996)). MMP-9 is elevated in CSF of MS patients and is detected by immunochemistry in active and chronic lesions. In autopsied samples from normal brain, MMP-like immunoreactivity (MMP-1, -2, -3 and -9) is localized to microglia and astrocytes. In MS patient samples, MMP expression is up-regulated in these glial cells and also in perivascular macrophages that are present in active brain lesion. (Chandler et al., J. Neuroimmunology, 72, 155-61 (1997); Liedtke et al., Annals of Neurology, 44, 35-46 (1998).)
In addition to the foregoing, MMP""s have been associated with neuronal degeneration in a number of animal models. These models can be used in an MMP inhibitor program to track inhibitor activity and predict pre-clinical efficacy. After focal ischemia in rats, MMP-9 was shown to increase in the infarcted area during the first day (Rosenberg et al., J. Cerebral Blood Flow and Metabolism, 16, 360-6, (1996)). MMP-2 remained the same until 5 days after injury when it increased significantly. This time course of induction is very similar to that seen by Clark et al, supra, in human clinical stroke samples. (Rosenberg and Navratil, Neurology, 48, 921-6 (1997)) have also shown that metalloproteinase inhibition blocks edema in intracerebral hemorrhage in the rat. A model of direct injection of MMP""s into the rat brain also demonstrated neuronal loss after MMP-9 or -2, but not MMP-8, injection as well as the loss of GFAP and myelin immunoreactivity (Anthony et al., J. Neuroimmunology, 87, 62-72 (1998)).
MMP-9 was detected in the CSF of mice with Experimental Autoimmune Encephelomyelitis (EAE), an animal model for MS. A hydroxamate inhibitor of MMP, GM6001, was found to suppress the development of, or reverse established, EAE (Gijbels, J. Clinical Invest., 94, 2177-82 (1994)). Based on this model, MMP inhibitors might act by preventing the influx of inflammatory cells across the basement membrane or ECM barrier that surrounds cerebral endothelium. Another hydroxamic acid-based compound which is a combined inhibitor of MMP and TNF-xcex1 processing/release, BB-1101 (Redford et al., Brain, 120, 1895-905 (1997)), attenuates Experimental Autoimmune Neuritis (EAN), a model of Guillain-Barre syndrome.
Lastly, in vitro experiments suggest a role for MMP""s in the development or progression of neuritic plaques. Deb and Gottschall, J. Neurochemistry, 66, 1641-7 (1996)), demonstrated that Axcex2 induces MMP-9 and -2 expression in astrocyte and mixed hippocampal cultures. Further, MMP-9 induction by Axcex2 in rat microglia can be inhibited by the anti-inflammatory agents dexamethasone and indomethacin (Gottschall, Neuroreport, 7, 3077-80 (1996)). This is of particular importance when considered in conjunction with clinical data which suggests that administration of anti-inflammatory drugs may slow the progression of AD (Rogers et al., Arzneimittelforschung, 45, 439-42 (1995)).
Applicants now disclose a method of treatment of diseases, conditions or disorders of the peripheral and central nervous system, including but not limited to Alzheimer""s disease, stroke/cerebral ischemia, head trauma, spinal cord injury, multiple sclerosis, amyotrophic lateral sclerosis, Huntington""s disease, Parkinson""s disease, migraine, cerebral amyloid angiopathy, AIDS, age-related cognitive decline; mild cognitive impairment and prion diseases, comprising the administration of small molecule inhibitors of MMP-9, MMP-2 or mixed MMP inhibitors which may reduce neuronal damage and limit neuroinflammation.
However, the diseases in which inhibition of MMP""s will provide therapeutic benefit include but are not limited to: arthritis (including osteoarthritis and rheumatoid arthritis), inflammatory bowel disease, Crohn""s disease, emphysema, acute respiratory distress syndrome, asthma chronic obstructive pulmonary disease, Alzheimer""s disease, organ transplant toxicity; cachexia, allergic reactions, allergic contact hypersensitivity, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, loosening of artificial joint implants, atherosclerosis (including atherosclerotic plaque rupture), aortic aneurysm (including abdominal aortic aneurysm and brain aortic aneurysm), congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury, neurodegenerative disorders (acute and chronic), inflammatory and autoimmune disorders, Huntington""s disease, Parkinson""s disease, migraine, depression, peripheral neuropathy, pain, cerebral amyloid angiopathy, nootropic or cognition enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, abnormal wound healing, bums, diabetes, tumor invasion, tumor growth, tumor metastasis, corneal scarring, scleritis, AIDS, sepsis, septic shock and other diseases characterized by metalloproteinase or ADAM expression. This invention also relates to methods of using the hydroxamic acid compounds described herein in the treatment of the above-identified diseases, conditions and disorders in mammals, especially humans, and to the pharmaceutical compositions containing these compounds useful in such methods.
It is recognized that different combinations of MMP""s are expressed in different pathological situations. As such inhibitors with specific selectivities for individual MMP""s may be preferred for individual diseases.
The present invention relates to a method of treating a disease or disorder of the peripheral or central nervous system, including but not limited to Alzheimer""s disease, stroke/cerebral ischemia, head trauma, spinal cord injury, multiple sclerosis, amyotrophic lateral sclerosis, Huntington""s disease, Parkinson""s disease, migraine, cerebral amyloid angiopathy, AIDS, age-related cognitive decline; mild cognitive impairment and prion diseases in a mammal, which comprises administering to said mammal a therapeutically effective amount of a compound of formula (I): 
or the pharmaceutically acceptable salts thereof, wherein
A is H or xe2x80x94(CH2)nxe2x80x94(Cxe2x95x90O)xe2x80x94Z; where n is 0 to 6; and Z is hydroxy, (C1-C6)alkoxy or NR1R2 wherein R1 and R2 are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, piperidyl, (C1-C6)alkylpiperidyl, (C6-C10)arylpiperidyl, (C2-C9)heteroarylpiperidyl, (C6-C10)aryl(C1-C6)alkylpiperidyl, (C2-C9)heteroaryl(C1-C6)alkylpiperidyl, (C1-C6)acylpiperidyl, (C6-C10)aryl, (C2-C9)heteroaryl, (C6-C10)aryl(C1-C6)alkyl, (C2-C9)heteroaryl(C1-C6)alkyl, (C6-C10)aryl(C6-C10)aryl, (C6-C10)aryl(C6-C10)aryl(C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C6)alkyl, R5(C2-C6)alkyl, (C1-C5)alkyl(CHR3)(C1-C6)alkyl wherein R3 is hydroxy, (C1-C6)acyloxy, (C1-C6)alkoxy, piperazino, (C1-C6)acylamino, (C1-C6)alkylthio, (C6-C10)arylthio, (C1-C6)alkylsulfinyl, (C6-C10)arylsulfinyl, (C1-C6)alkylsulfoxyl, (C6-C10)arylsulfoxyl, amino, (C1-C6)alkylamino, ((C1-C6)alkyl)2 amino, (C1-C6)acylpiperazino, (C1-C6)alkylpiperazino, (C6-C10)aryl(C1-C6)alkylpiperazino, (C2-C9)heteroaryl(C1-C6)alkylpiperazino, morpholino, thiomorpholino, piperidino or pyrrolidino; R4(C1-C6)alkyl, (C1-C5)alkyl(CHR4)(C1-C6)alkyl wherein R4 is piperidyl, (C1-C6)alkylpiperidyl, (C6-C10)arylpiperidyl, (C6-C10)aryl(C1-C6)alkylpiperidyl, (C2-C9)heteroarylpiperidyl or (C2-C9)heteroaryl(C1-C6)alkylpiperidyl; and CH(R5)COR6 wherein R5 is hydrogen, (C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl, (C2-C9)heteroaryl(C1-C6)alkyl, (C1-C6)alkylthio(C1-C6)alkyl, (C6-C10)arylthio(C1-C6)alkyl, (C1-C6)alkylsulfinyl(C1-C6)alkyl, (C6-C10)arylsulfinyl(C1-C6)alkyl, (C1-C6)alkylsulfonyl(C1-C6)alkyl, (C6-C10)arylsulfonyl(C1-C6)alkyl, hydroxy(Cl-C6)alkyl, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, ((C1-C6)alkylamino)2(C1-C6)alkyl, R7R8NCO(C1-C6)alkyl or R7OCO(C1-C6)alkyl wherein R7 and R8 are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl and (C2-C9)heteroaryl(C1-C6)alkyl; and R6 is R9O or R9R10N wherein R9 and R10 are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl and (C2-C9)heteroaryl(C1-C6)alkyl;
or R1 and R2, or R7 and R8, or R9 and R10 may be taken together to form an azetidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, (C1-C6)acylpiperazinyl, (C1-C6)alkylpiperazinyl, (C6-C10)arylpiperazinyl, (C2-C9)heteroarylpiperazinyl or a bridged diazabicycloalkyl ring selected from the group consisting of: 
xe2x80x83wherein p is 1, 2 or 3;
q is 1 or 2;
r is 0 or 1;
L is hydrogen, (C1-C3)alkyl or (C1-C6)acyl;
X1 and X2 are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, trifluoromethyl, trifluoromethyl(C1-C6)alkyl, (C1-C6)alkyl (difluoromethylene), (C1-C3)alkyl(difluoromethylene)(C1-C3)alkyl, (C6-C10)aryl, (C2-C9)heteroaryl, (C6-C10)aryl(C1-C6)alkyl, (C2-C9)heteroaryl(C1-C6)alkyl, (C6-C10)aryl(C6-C10)aryl, (C6-C10)aryl(C6-C10)aryl(C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C1-C6)acyloxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, piperazinyl(C1-C6)alkyl, (C1-C6)acylamino(C1-C6)alkyl, piperidyl, (C1-C6)alkylpiperidyl, (C6-C10)aryl(C1-C6)alkoxy(C1-C6)alkyl, (C2-C9)heteroaryl(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkylthio(C1-C6)alkyl, (C6-C10)arylthio(C1-C6)alkyl, (C1-C6)alkylsulfinyl(C1-C6)alkyl, (C6-C10)arylsulfinyl(C1-C6)alkyl, (C1-C6)alkylsulfonyl(C1-C6)alkyl, (C6-C10)arylsulfonyl(C1-C6)alkyl, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, ((C1-C6)alkylamino)2(C1-C6)alkyl, R11CO(C1-C6)alkyl wherein R11 is R12O or R12R13N wherein R12 and R13 are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl or (C2-C9)heteroaryl(C1-C6)alkyl; and R14(C1-C6)alkyl wherein R14 is (C1-C6)acylpiperazino, (C6-C10)arylpiperazino, (C2-C9)heteroarylpiperazino, (C1-C6)alkylpiperazino, (C6-C10)aryl(C1-C6)alkylpiperazino, (C2-C9)heteroaryl(C1-C6)alkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (C1-C6)alkylpiperidyl, (C6-C10)arylpiperidyl, (C2-C9)heteroarylpiperidyl, (C6-C10)aryl(C1-C6)alkylpiperidyl, (C2-C9)heteroaryl(C1-C6)alkylpiperidyl or (C1-C6)acylpiperidyl;
or X1 and X2 may be taken together to form a (C3-C6)cycloalkyl, a benzo-fused (C3-C6)cycloalkyl ring or a group of the formula (J7): 
xe2x80x83wherein the carbon atom bearing the asterisk is the carbon to which X1 and X2 are attached, s and t are each independently 1 or 2, and W is CF2, O, S, SO2 or NR15, wherein R15 is hydrogen, (C1-C6)alkyl, (C6-C10)acyl, (C6-C10)aryl, (C2-C9)heteroaryl, (C6-C10)aryl(C1-C6)alkyl, (C2-C9)heteroaryl(C1-C6)alkyl, (C1-C6)alkylsulfonyl, (C6-C10)arylsulfonyl or (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94;
Q is (C1-C6)alkyl, (C6-C10)aryl, (C6-C10)aryloxy(C6-C10)aryl, (C6-C10)aryl(C6-C10)aryl, (C6-C10)aryl(C6-C10)aryl(C1-C6)alkyl, (C6-C10)aryl(C2-C9)heteroaryl, (C6-C10)aryloxy(C2-C9)heteroaryl, (C2-C9)heteroaryl, (C2-C9)heteroaryl(C2-C9)heteroaryl, (C2-C9)heteroaryl(C6-C10)aryl, (C1-C6)alkyl(C6-C10)aryl, (C1-C6)alkoxy(C6-C10)aryl, ((C1-C6)alkoxy)2(C6-C10)aryl, (C6-C10)aryl(C1-C6)alkoxy(C6-C10)aryl, (C6-C10)aryl(C1-C6)alkoxy(C1-C6)alkyl, (C2-C9)heteroaryloxy(C6-C10)aryl, (C1-C6)alkyl(C2-C9)heteroaryl, (C1-C6)alkoxy(C2-C9)heteroaryl, ((C1-C6)alkoxy)2(C2-C9)heteroaryl, (C6-C10)aryl(C1-C6)alkoxy(C2-C9)heteroaryl, (C2-C9)heteroaryloxy(C2-C9)heteroaryl, (C6-C10)aryloxy(C1-C6)alkyl, (C2-C9)heteroaryloxy(C1-C6)alkyl, (C1-C6)alkyl(C6-C10)aryloxy(C6-C10)aryl, (C1-C6)alkyl(C2-C9)heteroaryloxy(C6-C10)aryl, (C1-C6)alkyl(C6-C10)aryloxy(C2-C9)heteroaryl, (C1-C6)alkoxy(C6-C10)aryloxy(C6-C10)aryl, (C1-C6)alkoxy(C2-C9)heteroaryloxy(C6-C10)aryl or (C1-C6)alkoxy(C6-C10)aryloxy(C2-C9)heteroaryl, wherein each of the foregoing aryl groups may be optionally substituted by fluoro, chloro, bromo, trifluoromethyl, trifluoromethoxy, difluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy or perfluoro(C1-C3)alkyl;
with the proviso that when either X1 or X2 is CH(R5)COR6 wherein R5 and R6 are as defined above, the other of X1 or X2 is hydrogen, (C1-C6)alkyl or benzyl.
One preferred embodiment of the present invention relates to a method of treating a disease, disorder or condition of the peripheral or central nervous system in a mammal, comprising the administration to a mammal a therapeutically effective amount of a compound of the formula (Ia): 
or a pharmaceutically acceptable salt thereof, wherein X1, X2, Q and Z are as defined above, and n is an integer from 1 to 6.
Preferred methods of the invention comprise the administration of a compound of formula (Ia) wherein n is 2. Other preferred methods of the invention comprise the administration of a compound of formula (Ia) wherein Q is 4-methoxyphenyl or 4-phenoxyphenyl, optionally substituted by fluoro, chloro, bromo, trifluoromethyl, trifluoromethoxy, difluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy or perfluoro(C1-C3)alkyl. Other preferred methods of the invention comprise the administration of a compound of formula (Ia) wherein either X1 or X2 is not hydrogen. Other preferred methods of the invention comprise the administration of a compound of formula (Ia) wherein Z is hydroxy, Q is 4-methoxyphenyl or 4-phenoxyphenyl, optionally substituted by fluoro, chloro, bromo, trifluoromethyl, trifluoromethoxy, difluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy or perfluoro(C1-C3)alkyl, and either X1 or X2 is not hydrogen.
Other preferred methods of the invention comprise the administration of a compound of formula (Ia) wherein Q is 4-methoxyphenyl or 4-phenoxyphenyl and X1 and X2 are taken together to form (C3-C6)cycloalkyl, oxacyclohexanyl, thiocyclohexanyl, indanyl or a group of the formula: 
wherein the carbon bearing the asterisk is the carbon to which X1 and X2 are attached and R15 is (C1-C6)acyl, (C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl, (C2-C9)heteroaryl(C1-C6)alkyl or (C1-C6)alkylsulfonyl.
A more preferred embodiment of the present invention relates to a method of treating a disease, condition or disorder of the peripheral or central nervous system in a mammal comprising the administration of a therapeutically effective amount of a compound of the formula (Ic): 
or the pharmaceutically acceptable salts thereof, wherein
X1 is (C1-C6)alkyl;
X2 is (C1-C6)alkyl; or
X1 and X2 taken together with the carbon atom to which they are attached form a ring selected from (C5-C7)cycloalkyl , 4-tetrahydropyranyl and 4-piperidinyl;
Z is hydroxy or (C1-C6)alkoxy; and
Y is a substituent on any of the carbon atoms of the phenyl ring capable of supporting an additional bond, preferably from 1 to 2 substituents (more preferably one substituent, most preferably one substituent in the 4-position) on the phenyl ring, independently selected from hydrogen, fluoro, chloro, trifluoromethyl, (C1-C6)alkoxy, trifluoromethoxy, difluoromethoxy and (C1-C6)alkyl.
The more preferred methods of the invention comprise the administration of a compound of formula (Ic) wherein Y is hydrogen, fluoro or chloro, preferably 4-fluoro or 4-chloro. Other more preferred methods comprise the administration of a compound of formula (Ic) wherein X1 and x2 taken together with the carbon atom to which they are attached form a cyclopentyl or 4-tetrahydropyranyl ring.
Other preferred methods of the invention comprise the administration of a compound of formula (Ic) wherein X1 and X2 are both methyl. Other preferred methods comprise the administration of a compound of formula (Ic) wherein Z is hydroxy.
Specifically, the most preferred methods of the invention comprise the administration of a compound of formula (Ic) selected from the group consisting of:
3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(1-hydroxycarbamoylcyclopentyl)amino]-propionic acid ethyl ester;
3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(1-hydroxycarbamoylcyclopentyl)amino]propionic acid;
3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(1-hydroxycarbamoyl-1-methylethyl)amino]propionic acid ethyl ester;
3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(1-hydroxycarbamoyl-1-methylethyl)amino]propionic acid;
3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(4-hydroxycarbamoyltetrahydropyran-4-yl)-amino]propionic acid;
3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(4-hydroxycarbamoyltetrahydropyran-4-yl)-amino]propionic acid ethyl ester;
3-[[4-(4-chlorophenoxy)benzenesulfonyl]-(4-hydroxycarbamoyltetrahydropyran-4-yl)-amino]propionic acid;
3-[[4-(4-chlorophenoxy)benzenesulfonyl]-(4-hydroxycarbamoyltetrahydropyran-4-yl)-amino]propionic acid ethyl ester;
3-[(4-hydroxycarbamoyltetrahydropyran-4-yl)-(4-phenoxybenzenesulfonyl)amino]-propionic acid;
3-[(4-hydroxycarbamoyltetrahydropyran-4-yl)-(4-phenoxybenzenesulfonyl)amino]-propionic acid ethyl ester;
3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(4-hydroxycarbamoylpiperidin-4-yl)-amino]propionic acid ethyl ester;
3-[[4-(4-chlorophenoxy)benzenesulfonyl]-(1-hydroxycarbamoyl-1-methylethyl)amino]-propionic acid;
3-[[4-(4-chlorophenoxy)benzenesulfonyl]-(1-hydroxycarbamoyl-1-methylethyl)amino]-propionic acid ethyl ester;
3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(1-hydroxycarbamoylcyclohexyl)amino]-propionic acid;
3-[(1-hydroxycarbamoylcyclopentyl)-(4-phenoxybenzenesulfonyl)amino]propionic acid;
3-[[4-(4-chlorophenoxy)benzenesulfonyl]-(1-hydroxycarbamoylcyclopentyl)amino]-propionic acid
and pharmaceutically acceptable salts thereof.
The methods of the invention also encompass methods of treating or preventing comprising administering a prodrug of a compound of formula (I). A compound of formula (I) having a free amino, amido, hydroxy or carboxylic acid group can be converted into a prodrug. Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues which are covalently joined through peptide bonds to free amino, hydroxy or carboxylic acid groups of compounds of formula (I). The amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline homocysteine, homoserine, omithine and methionine sulfone. Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters which are covalently bonded to the above substituents of formula (I) through the carbonyl carbon prodrug sidechain. Prodrugs also include compounds of formula (I) in which the hydroxamic acid and carbonyl moiety when taken together, for example, form a group of the formula (Id): 
wherein X1, X2 and Y are as defined above and U and V are independently carbonyl, methylene, SO2 or SO3, and b is an integer from one to three wherein each methylene group is optionally substituted with hydroxy.
In addition to the foregoing preferred methods, further preferred embodiments of the present invention relates to a method of treatment of a condition, disease or disorder of the peripheral or central nervous system in a mammal comprising the administration of a compound of the formula (Ib): 
wherein X1, X2 and Q are as defined above.
Other preferred methods comprise the administration of a compound of formula (Ib) wherein X1 and x2 are taken together to form a (C3-C6)cycloalkyl or benzo-fused (C3-C6)cycloalkyl ring or a group of formula J7: 
wherein the carbon atom bearing the asterisk is the carbon to which X1 and X2 are attached, s and t are independently 1 or 2; W is CF2, S, O or NR16 and R16 is hydrogen, (C1-C6)alkyl, (C6-C10)aryl, (C2-C9)heteroaryl, (C6-C10)aryl(C1-C6)alkyl, (C2-C9)heteroaryl(C1-C6)alkyl, (C1-C6)alkylsulfonyl, (C6-C10)arylsulfonyl or acyl.
Other preferred methods comprise the administration of a compound of formula (Ib) wherein X1 and X2 are taken together to form a (C3-C6)cycloalkyl or benzo-fused (C3-C6)cycloalkyl ring. Other preferred methods comprise the administration of a compound of formula (Ib) wherein Q is (C6-C10)aryl, (C6-C10)aryl(C6-C10)aryl, (C6-C10)aryloxy(C6-C10)aryl, (C6-C10)aryloxy(C2-C9)heteroaryl, (C2-C9)heteroaryl, (C2-C9)heteroaryl(C2-C9)heteroaryl, (C6-C10)aryl(C2-C9)heteroaryl, (C2-C9)heteroaryl(C6-C10)aryl or (C2-C9)heteroaryloxy(C6-C10)aryl. Other preferred methods comprise the administration of a compound of formula (Ib) wherein Q is (C6-C10)aryloxy(C6-C10)aryl. Other preferred methods comprise the administration of a compound of formula (Ib) wherein X1 and X2 are each independently (C1-C6)alkyl.
Other more preferred methods comprise the administration of a compound of formula (Ib) wherein X1 and X2 are taken together to form a (C3-C6)cycloalkyl or benzo-fused (C3-C6)cycloalkyl ring or a group of the formula (J7): 
wherein the carbon atom bearing the asterisk is the carbon to which X1 and X2 are attached, s and t are independently 1 or 2 and Q9 is CF2, S, O or NR16 wherein R16 is hydrogen, (C1-C6)alkyl, (C6-C10)aryl, (C2-C9)heteroaryl, (C6-C10)aryl(C1-C6)alkyl, (C2-C9)heteroaryl(C1-C6)alkyl, (C1-C6)alkylsulfonyl, (C6-C10)arylsulfonyl or acyl; and Q is (C6-C10)aryl, (C6-C10)aryl(C6-C10)aryl, (C6-C10)aryloxy(C6-C10)aryl, (C6-C10)aryloxy-(C2-C9)heteroaryl, (C2-C9)heteroaryl, (C2-C9)heteroaryl(C2-C9)heteroaryl, (C6-C10)aryl(C2-C9)heteroaryl, (C2-C9)heteroaryl(C6-C10)aryl or (C2-C9)heteroaryloxy(C6-C10)aryl.
More preferred methods comprise the administration of a compound of formula (Ib) wherein X1 and X2 are taken together to form a (C3-C6)cycloalkyl or benzo-fused (C3-C6)cycloalkyl ring; and Q is (C6-C10)aryl, (C6-C10)aryl(C6-C10)aryl, (C6-C10)aryloxy(C6-C10)aryl, (C6-C10)aryloxy(C2-C9)heteroaryl, (C2-C9)heteroaryl, (C2-C9)heteroaryl(C2-C9)heteroaryl, (C6-C10)aryl(C2-C9)heteroaryl, (C2-C9)heteroaryl(C6-C10)aryl or (C2-C9)heteroaryloxy(C6-C10)aryl.
More preferred methods comprise the administration of a compound of formula (Ib) wherein X1 and X2 are each independently (C1-C6)alkyl; and Q is (C6-C10)aryl, (C6-C10)aryl(C6-C10)aryl, (C6-C10)aryloxy(C6-C10)aryl, (C6-C10)heteroaryl, (C2-C9)heteroaryl, (C2-C9)heteroaryl(C2-C9)heteroaryl, (C6-C10)aryl(C2-C9)heyeroaryl, (C2-C9)heteroaryl(C6-C10)aryl or (C2-C9)heteroaryloxy(C6-C10)aryl. More preferred methods utilize compounds of formula (Ib) wherein X1 and X2 are each independently (C1-C6)alkyl; and Q is (C6-C10)aryloxy(C6-C10)aryl.
Further, in addition to the methods stated above, other preferred methods comprise the administration of a compound of formula (Ia), supra, wherein n is 1 and either of R1 or R2 is hydrogen. Other preferred methods comprise the administration of a compound of formula (Ia) wherein Z is alkoxy, Q is 4-methoxyphenyl or 4-phenoxyphenyl and either X1 or X2 is not hydrogen. More preferred methods comprise the administration of a compound of formula (Ia) wherein n is 2, Q is 4-methoxyphenyl or 4-phenoxyphenyl, R1 and R2 taken together to form piperazinyl, (C1-C6)alkylpiperazinyl, (C6-C10)aryl piperazinyl or (C2-C9)heteroaryl(C1-C6)alkylpiperazinyl, and either X1 or X2 is not hydrogen or both X1 and X2 are not hydrogen. More preferred methods comprise the administration of a compound of formula (Ia) wherein n is 2, Q is 4-methoxyphenyl or 4-phenoxyphenyl, R1 is hydrogen or (C1-C6)alkyl, R2 is 2-pyridylmethyl, 3-pyridylmethyl or 4-pyridylmethyl, and either X1 or X2 is not hydrogen or both X1 and X2 are not hydrogen. More preferred methods comprise the administration of a compound of formula (Ia) wherein n is 1, Q is 4-methoxyphenyl or 4-phenoxyphenyl, R1 is hydrogen, R2 is 2-pyridylmethyl, 3-pyridylmethyl or 4-pyridylmethyl, and either X1 or X2 is not hydrogen or both X1 and X2 are not hydrogen. More preferred methods comprise the administration of a compound of formula (Ia) wherein n is 2, Q is 4-methyoxyphenyl, R1 is hydrogen or (C1-C6)alkyl and R2 is R3(C2-C6)alkyl wherein R3 is morpholino, thiomorpholino, piperidino, pyrrolidino, (C1-C6)acylpiperazino, (C1-C6)akylpiperazino, (C6-C10)arylpiperazino, (C2-C9)heteroarylpiperazino, (C6-C10)aryl(C1-C6)alkylpiperazino or (C2-C9)heteroaryl(C1-C6)alkylpiperazino and either X1 or X2 is not hydrogen or both X1 and X2 are not hydrogen. More preferred methods comprise the administration of a compound of formula (Ia) wherein n is 1, Q is 4-methoxyphenyl or 4-phenoxyphenyl, R1 is hydrogen, R2 is R3(C2-C6)alkyl wherein R3 is morpholino, thiomorpholino, piperidino, pyrrolidino, (C1-C6)acylpiperazino, (C1-C6)akylpiperazino, (C6-C10)arylpiperazino, (C2-C9)heteroarylpiperazino, (C6-C10)aryl(C1-C6)alkylpiperazino or (C2-C9)heteroaryl(C1-C6)alkylpiperazino, and either X1 or X2 is not hydrogen or both X1 and X2 are not hydrogen.
In the foregoing discussion, the term xe2x80x9calkylxe2x80x9d, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
The term xe2x80x9calkoxyxe2x80x9d, as used herein, includes O-alkyl groups wherein xe2x80x9calkylxe2x80x9d is as defined above.
The term xe2x80x9carylxe2x80x9d, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl, optionally substituted by 1 to 3 substituents selected from the group consisting of fluoro, chloro, bromo, perfluoro(C1-C6)alkyl (including trifluoromethyl), (C1-C6)alkoxy, (C6-C10)aryloxy, perfluoro(C1-C3)alkoxy (including trifluoromethoxy and difluoromethoxy) and (C1-C6)alkyl.
The term xe2x80x9cheteroarylxe2x80x9d, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic heterocyclic compound by removal of one hydrogen, such as pyridyl, furyl, pyrrolyl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, indolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benzthiazolyl or benzoxazolyl, optionally substituted by 1 to 2 substituents selected from the group consisting of fluoro, chloro, trifluoromethyl, (C1-C6)alkoxy, (C6-C10)aryloxy, trifluoromethoxy, difluoromethoxy and (C1-C6)alkyl. Preferred heteroaryl groups include pyridyl, furyl, thienyl, isothiazolyl, pyrazinyl, pyrimidyl, pyrazolyl, isoxazolyl, thiazolyl or oxazolyl. Most preferred heteroaryl groups include pyridyl, furyl or thienyl.
The term xe2x80x9cacylxe2x80x9d, as used herein, unless otherwise indicated, includes a radical of the general formula RCO wherein R is alkyl, alkoxy, aryl, arylalkyl or arylalkyloxy and the terms xe2x80x9calkylxe2x80x9d or xe2x80x9carylxe2x80x9d are as defined above.
The term xe2x80x9cacyloxyxe2x80x9d, as used herein, includes O-acyl groups wherein xe2x80x9cacylxe2x80x9d is defined above.
The term xe2x80x9ctreatingxe2x80x9d refers to, and includes, reversing, alleviating, inhibiting the progress of, or preventing a disease, disorder or condition, or one or more symptoms thereof; and xe2x80x9ctreatmentxe2x80x9d and xe2x80x9ctherapeuticallyxe2x80x9d refer to the act of treating, as defined above.
A xe2x80x9ctherapeutically effective amountxe2x80x9d is any amount of any of the compounds utilized in the course of practicing the invention provided herein that is sufficient to reverse, alleviate, inhibit the progress of, or prevent a disease, disorder or condition, or one or more symptoms thereof.
The methods of the invention comprise the administration of a compound of formula (I) which may have chiral centers and therefore exist in different enantiomeric forms. This invention relates to all optical isomers, tautomers and stereoisomers of the compounds of formula (I) and mixtures thereof.
The present invention also relates to a method comprising the administration of a pharmaceutically acceptable acid addition salt of a compound of the formula (I). The possible acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1xe2x80x2-methylene-bis-(2-hydroxy-3-naphthoate)) salts.
The invention also relates to a method comprising the administration of a base addition salt of a compound of formula (I). The chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of formula (I) that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.
The subject invention also relates to a method of treatment which relates to isotopically-labeled compounds, which are identical to those recited in formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds relating to the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 15O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. Compounds relating to the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.
The present invention also relates to a pharmaceutical composition for the treatment of a disease, condition or disorder of the peripheral or central nervous system, wherein the disease, condition or disorder is Alzheimer""s disease, stroke/cerebral ischemia, head trauma, spinal cord injury, multiple sclerosis, amyotrophic lateral sclerosis, Huntington""s disease, Parkinson""s disease, migraine, cerebral amyloid angiopathy, AIDS, age-related cognitive decline; mild cognitive impairment or a prion disease.
The present invention also relates to a pharmaceutical composition for treating of a disease, disorder or condition, wherein the disease, condition or disorder is arthritis (including osteoarthritis and rheumatoid arthritis), inflammatory bowel disease, Crohn""s disease, emphysema, chronic obstructive pulmonary disease, Alzheimer""s disease, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, loosening of artificial joint implants, atherosclerosis (including atherosclerotic plaque rupture), aortic aneurysm (including abdominal aortic aneurysm and brain aortic aneurysm), congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury, neurodegenerative disorders (acute and chronic), inflammatory and autoimmune disorders, Huntington""s disease, Parkinson""s disease, migraine, depression, peripheral neuropathy, pain, cerebral amyloid angiopathy, nootropic or cognition enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, comeal injury, macular degeneration, abnormal wound healing, burns, diabetes, tumor invasion, tumor growth, tumor metastasis, corneal scarring, scleritis, AIDS, sepsis, septic shock, other diseases characterized by metalloproteinase activity or other diseases characterized by mammalian reprolysin activity in a mammal, including a human, comprising an amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof effective in such treatments and a pharmaceutically acceptable carrier.
This invention also encompasses pharmaceutical compositions containing a prodrug of a compound of the formula (I). This invention also encompasses methods of treating or preventing disorders that can be treated or prevented by the inhibition of matrix metalloproteinases or the inhibition of mammalian reprolysin comprising a administering prodrug of compounds of the formula (I). A compound of formula (I) having a free amino, amido, hydroxy or carboxylic group can be converted into a prodrug. Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues which are covalently joined through peptide bonds to free amino, hydroxy or carboxylic acid groups of compounds of formula (I). The amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, omithine and methionine sulfone. Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters which are covalently bonded to the above substituents of formula I through the carbonyl carbon prodrug side chain.
One of ordinary skill in the art will appreciate that the methods of the invention are useful in treating a diverse array of diseases. One of ordinary skill in the art will also appreciate that when using the methods of the invention in the treatment of a specific disease that the methods of the invention may be combined with various existing therapeutic methods and agents used for that disease.
The present invention also relates to combination therapies using, or combination pharmaceutical compositions comprising, a compound of formula (I) and, e.g., a standard non-steroidal anti-inflammatory drug (NSAID""S), such as piroxicam, diclofenac, a propionic acid, such as naproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen, a fenamate, such as mefenamic acid, indomethacin, sulindac, apazone, a pyrazolone, such as phenylbutazone; a salicylate, such as aspirin; an analgesic or intraarticular therapy, such as a corticosteroid and a hyaluronic acid, such as hyalgan and synvisc; an immune suppressant, such as cyclosporin, interferon, etc., e.g., in organ transplant therapy; a TNF-xcex1 inhibitor agent, such as an anti-TNF monoclonal antibody, a TNF receptor immunoglobulin molecule (such as Enbrel(copyright)), low dose methotrexate, lefunimide, hydroxychloroquine, d-penicilamine, auranofin, parenteral gold, oral gold, etc.
The methods of present invention also relate to combination therapies using or combination pharmaceutical compositions comprising, a compound of formula (I) and, e.g., a CNS agent or agents, such as an antidepressant (e.g., sertraline, fluoxetine, paroxetine, etc.); an anti-Parkinsonian drug, such as deprenyl, L-dopa, requip, miratex, etc.; a MAOB inhibitor, such as selegine, rasagiline, etc.; a COMP inhibitor, such as tolcapone (i.e., Tasmar); an A-2 inhibitor; a dopamine reuptake inhibitor; an NMDA antagonist; a nicotine agonist; a dopamine agonist; an inhibitor of neuronal nitric oxide synthase; an anti-Alzheimer""s drug; an acetylcholinesterase inhibitor, such as metrifonate, donepezil (i.e., Aricept), Exelon (i.e., ENA 713 or rivastigmine), etc.; tetrahydroaminoacridine (i.e., Tacrine, Cognex, or THA); a COX-1 or COX-2 inhibitor, such as celecoxib (i.e., Celebrex), rofecoxib (i.e., Vioxx), etc.; propentofylline; an anti-stroke medication; an NR2B selective antagonist; a glycine site antagonist; a neutrophil inhibitory factor (NIF), etc. The methods of the present invention further relate to combination therapies using, or combination pharmaceutical compositions comprising, a compound of formula (I) and, e.g., an estrogen; a selective estrogen modulator, such as estrogen, raloxifene, tamoxifene, droloxifene, lasofoxifene, etc. The methods of the present invention also relate to combination therapies using, or combination pharmaceutical compositions comprising, a compound of formula (I) and, e.g., an agent that results in reduction of Axcex21-40/1-42, such as an amyloid aggregation inhibitor, a secretase inhibitor, etc.
Further, the methods of present invention also relate to combination therapies using, or combination pharmaceutical compositions comprising, a compound of formula (I) and, e.g., an osteoporosis agents such as droloxifene or fosomax and immunosuppressant agents such as FK-506 and rapamycin. The methods of present invention also relate to combination therapies using, or combination pharmaceutical compositions comprising, a compound of formula (I) and, e.g., an anticancer agent, such as endostatin and angiostatin; a cytotoxic drug, such as adriamycin, daunomycin, cis-platinum, etoposide, taxol, taxotere or an alkaloid, such as vincristine; an antimetabolite, such as methotrexate; a cardiovascular agent, such as calcium channel blockers; a lipid lowering agent, such as a statin, a fibrate, a beta-blocker, an ACE inhibitor, an angiotensin-2 receptor antagonist or a platelet aggregation inhibitor. The methods of present invention also relate to combination therapies comprising the administration of compounds of formula (I) and another treatment, such as, e.g., fetal implant surgery treatment, gene therapy, etc.